Serious problems associated with cancer chemotherapy include intrinsic resistance to an anticancer drug, which invalidates the effect of the anticancer drug from the beginning of cancer therapy, and development of acquired resistance to an anticancer drug (i.e., reduction of the effect of the drug, which is caused by long-term continuous administration thereof). Overcoming such anticancer drug resistance has been envisaged to lead to improvement of the performance of cancer chemotherapy, and thus attempts have been made to elucidate various resistance mechanisms. Particularly, expression of a drug transporter, which actively transports an anticancer drug out of cancer cells, thereby reducing the amount of intracellular accumulation of the drug, is considered to play an important role in such a resistance mechanism.
Particularly, P-glycoprotein, which is a drug transporter discovered in the 1970s, and is encoded by an MDR1 gene, has been considered a potent target molecule of a multidrug-resistance-overcoming agent, since this protein causes cross-resistance to a plurality of anticancer drugs having different chemical structures and action mechanisms. However, it has been gradually elucidated that a drug transporter other than P-glycoprotein is also associated with an anticancer drug resistance mechanism, and demand has arisen for development of a resistance-overcoming agent which targets such a drug transporter.
Under such circumstances, there was discovered, in 1998, breast cancer resistance protein (BCRP), which is a drug transporter belonging to a group which is called “ATP-binding cassette (ABC) transporter superfamily” to which P-glycoprotein also belongs (see Proc. Natl. Acad. Sci. USA 95, 15665-15670 (1998)). BCRP has a structure including only one ATP-binding cassette, which differs from that of P-glycoprotein or another drug transporter, which has two ATP-binding cassettes. BCRP is intimately involved in the mechanism of resistance to a topoisomerase I inhibitor (e.g., irinotecan hydrochloride (CPT-11) or topotecan) or to a topoisomerase II inhibitor (e.g., mitoxantrone). Meanwhile, BCRP has been elucidated to exhibit substrate specificity different from that of P-glycoprotein, since BCRP does not act on, for example, paclitaxel or vincristine, which is excreted by P-glycoprotein, and BCRP is involved in excretion of a camptothecin derivative (e.g., CPT-11 or 7-ethyl-10-hydroxycamptothecin (SN-38: active metabolite of CPT-11)), which is rarely excreted extracellularly by P-glycoprotein (see Cancer Res. 59, 5938-5946 (1999)). In addition, BCRP has been suggested to be involved in the limitation of the bioavailability of an orally administered anticancer drug (see J. Clin. Oncol. 20, 2943-2950 (2002)). In view of the foregoing, demand has arisen for development of a BCRP inhibitor, which is envisaged to exhibit the effect of overcoming anticancer drug resistance that is not overcome by a conventional resistance-overcoming agent, and to improve the bioavailability of an anticancer drug.
Hitherto, a variety of P-glycoprotein inhibitors have been developed for the purpose of overcoming anticancer drug resistance. However, since few BCRP-specific inhibitors have been reported, and such inhibitors have been considered to exhibit unsatisfactory BCRP-inhibiting effect, demand has arisen for a drug which exhibits more potent BCRP-inhibiting effect (see Mol. Cancer. Ther. 1, 427-434 (2002)). Incidentally, some diphenylacrylonitrile derivatives have been reported to exhibit anticancer effect (see J. Med. Chem. 41, 3022-3032 (1998). However, a diphenylacrylonitrile derivative exhibiting anticancer-drug-resistance-overcoming effect or BCRP-inhibiting effect has not yet been known.
An object of the present invention is to provide a BCRP inhibitor.